A new perspective on the analysis of helix-helix packing preferences in globular proteins

For many years it had been believed that steric compatibility of helix interfaces could be the source of the observed preference for particular angles between neighbouring helices as emerging from statistical analysis of protein databanks. Several elegant models describing how side chains on helices can interdigitate without steric clashes were able to account quite reasonably for the observed distributions. However, it was later recognized (Bowie, 1997 and Walther, 1998) that the ``bare'' measured angle distribution should be corrected to avoid statistical bias. Disappointingly, the rescaled distributions dramatically lost their similarity with theoretical predictions casting many doubts on the validity of the geometrical assumptions and models. In this report we elucidate a few points concerning the proper choice of the random reference distribution. In particular we show the existence of crucial corrections due to the correct implementation of the approach used to discriminate whether two helices are in contact or not and to measure their relative orientations. By using this new rescaling, the ``true'' packing angle preferences are well described, even more than with the original ``bare'' distribution, by regular packing models.Comment: 23 pages, 5 figure

Simple solvation potential for coarse-grained models of proteins

We formulate a simple solvation potential based on a coarsed-grain representation of amino acids with two spheres modeling the $C_\alpha$ atom and an effective side-chain centroid. The potential relies on a new method for estimating the buried area of residues, based on counting the effective number of burying neighbours in a suitable way. This latter quantity shows a good correlation with the buried area of residues computed from all atom crystallographic structures. We check the discriminatory power of the solvation potential alone to identify the native fold of a protein from a set of decoys and show the potential to be considerably selective.Comment: 18 pages, 8 tables, 3 figure

Value of thermostatic loads in future low-carbon Great Britain system

This paper quantifies the value of a large population of heterogeneous thermostatically controlled loads (TCLs). The TCL dynamics are regulated by means of an advanced demand side response model (DSRM). It optimally determines the flexible energy/power consumption and simultaneously allocates multiple ancillary services. This model explicitly incorporates the control of dynamics of the TCL recovery pattern after the provision of the selected services. The proposed framework is integrated in a mixed integer linear programming formulation for a multi-stage stochastic unit commitment. The scheduling routine considers inertia-dependent frequency response requirements to deal with the drastic reduction of system inertia under future low-carbon scenarios. Case studies focus on the system operation cost and CO2 emissions reductions for individual TCLs for a) different future network scenarios, b) different frequency requirements, c) changes of TCL parameters (e.g. coefficient of performance, thermal insulation etc.)

Stochastic scheduling with inertia-dependent fast frequency response requirements

High penetration of wind generation will increase the requirement for fast frequency response services as currently wind plants do not provide inertial response. Although the importance of inertia reduction has been widely recognized, its impact on the system scheduling has not been fully investigated. In this context, this paper proposes a novel mixed integer linear programming (MILP) formulation for stochastic unit commitment that optimizes system operation by simultaneously scheduling energy production, standing/spinning reserves and inertia-dependent fast frequency response in light of uncertainties associated with wind production and generation outages. Post-fault dynamic frequency requirements, rate of change of frequency, frequency nadir and quasi-steady-state frequency are formulated as MILP constraints by using the simplified model of system dynamics. Moreover the proposed methodology enables the impact of wind uncertainty on system inertia to be considered. Case studies are carried out on the 2030 Great Britain system to demonstrate the importance of incorporating inertia-dependent fast frequency response in the stochastic scheduling and to indicate the potential for the proposed model to inform reviews of grid codes associated with fast frequency response and future development of inertia-related market

Continuum model for polymers with finite thickness

We consider the continuum limit of a recently-introduced model for discretized thick polymers, or tubes. We address both analytically and numerically how the polymer thickness influences the decay of tangent-tangent correlations and find how the persistence length scales with the thickness and the torsional rigidity of the tube centerline. At variance with the worm-like chain model, the phase diagram that we obtain for a continuous tube is richer; in particular, for a given polymer thickness there exists a threshold value for the centerline torsional rigidity separating a simple exponential decay of the tangent-tangent correlation from an oscillatory one.Comment: 8 pages, 4 figures. Accepted for publication in J. Phys.

Re: "Relation of the Traditional Mediterranean Diet to Cerebrovascular Disease in a Mediterranean Population"

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MIRU-VNTR genotyping of Mycobacterium tuberculosis strains using QIAxcel technology: a multicentre evaluation study

Molecular genotyping of M.tuberculosis is an important laboratory tool in the context of emerging drug resistant TB. The standard 24-loci MIRU-VNTR typing includes PCR amplification followed by the detection and sizing of PCR fragments using capillary electrophoresis on automated sequencers or using agarose gels. The QIAxcel Advanced system might offer a cost-effective medium-throughput alternative.Performance characteristics of the QIAxcel Advanced platform for the standard 24 VNTR loci panel was evaluated at two centres on a total of 140 DNA specimens using automated capillary electrophoresis as a reference method. Additionally 4 hypervariable MIRU-VNTR loci were evaluated on 53 crude DNA extracts. The sizing accuracy, interlaboratory reproducibility and overall instrument's performance were assessed during the study.An overall concordance with the reference method was high reaching 98.5% and 97.6% for diluted genomic and crude DNA extracts respectively. 91.4% of all discrepancies were observed in fragments longer than 700bp. The concordance for hypervariable loci was lower except for locus 4120 (96.2%). The interlaboratory reproducibility agreement rates were 98.9% and 91.3% for standard and hypervariable loci, respectively. Overall performance of the QIAxcel platform for M.tuberculosis genotyping using a panel of standard loci is comparable to that of established methods for PCR fragments up to 700bp. Inaccuracies in sizing of longer fragments could be resolved through using in-house size markers or introduction of offset values. To conclude, the QiaXcel system could be considered an effective alternative to existing methods in smaller reference and regional laboratories offering good performance and shorter turnaround times

Folding Rate Optimization Promotes Frustrated Interactions in Entangled Protein Structures

Many native structures of proteins accomodate complex topological motifs such as knots, lassos, and other geometrical entanglements. How proteins can fold quickly even in the presence of such topological obstacles is a debated question in structural biology. Recently, the hypothesis that energetic frustration might be a mechanism to avoid topological frustration has been put forward based on the empirical observation that loops involved in entanglements are stabilized by weak interactions between amino-acids at their extrema. To verify this idea, we use a toy lattice model for the folding of proteins into two almost identical structures, one entangled and one not. As expected, the folding time is longer when random sequences folds into the entangled structure. This holds also under an evolutionary pressure simulated by optimizing the folding time. It turns out that optmized protein sequences in the entangled structure are in fact characterized by frustrated interactions at the closures of entangled loops. This phenomenon is much less enhanced in the control case where the entanglement is not present. Our findings, which are in agreement with experimental observations, corroborate the idea that an evolutionary pressure shapes the folding funnel to avoid topological and kinetic traps

Preclinical atherosclerosis and metabolic syndrome increase cardio- and cerebrovascular events rate: a 20-year follow up

BACKGROUND: Intima-media thickness (IMT) is a validated marker of preclinical atherosclerosis and a predictor of cardiovascular events. PATIENTS: We studied a population of 529 asymptomatic patients (age 62\u2009\ub1\u200912.8 years), divided into two groups of subjects with and without Metabolic Syndrome (MetS). METHODS: All patients, at baseline, have had a carotid ultrasound evaluation and classified in two subgroups: the first one without atherosclerotic lesions and the second one with preclinical atherosclerosis (increased IMT or asymptomatic carotid plaque). Cardiovascular endpoints were investigated in a 20-years follow-up. RESULTS: There were 242 cardiovascular events: 144 among patients with MetS and 98 among in healthy controls (57.4% vs. 35.2%; P\u2009<\u20090.0001). 63 events occurred in patients with normal carotid arteries, while 179 events occurred in patients with preclinical atherosclerosis (31.8% vs. 54.1%; P\u2009<\u20090.0001). Of the 144 total events occurred in patients with MetS, 36 happened in the subgroup with normal carotid arteries and 108 in the subgroup with preclinical atherosclerosis (45% vs. 63.15%; P\u2009=\u20090.009). 98 events occurred in patients without MetS, of which 27 in the subgroup with normal carotid arteries and 71 in the subgroup with preclinical atherosclerosis (22.88% vs. 44.37%; P\u2009=\u20090.0003). In addition, considering the 63 total events occurred in patients without atherosclerotic lesions, 36 events were recorded in the subgroup with MetS and 27 events in the subgroup without MetS (45% vs. 22.88%; P\u2009=\u20090.0019). Finally, in 179 total events recorded in patients with preclinical carotid atherosclerosis, 108 happened in the subgroup with MetS and 71 happened in the subgroup without MetS (63.15% vs. 44.37%; P\u2009=\u20090.0009). The Kaplan-Meier function showed an improved survival in patients without atherosclerotic lesions compared with patients with carotid ultrasound alterations (P\u2009=\u20090.01, HR: 0.7366, CI: 0.5479 to 0.9904). CONCLUSIONS: Preclinical atherosclerosis leads to an increased risk of cardiovascular events, especially if it is associated with MetS